Agglomerates by crystallization

ABSTRACT

The present invention describes novel agglomerates in crystalline form of β-lactam compounds. Furthermore, a process for the preparation of said agglomerates, wherein a solution or suspension of at least one β-lactam compound in a solvent is mixed with one or more anti-solvents has been described.

FIELD OF THE INVENTION

The present invention describes agglomerates of β-lactam compounds incrystalline form and a process to prepare the same.

BACKGROUND OF THE INVENTION

β-Lactam antibiotics constitute the most important group of antibioticcompounds, with a long history of clinical use. Among this group, theprominent ones are the penicillins and cephalosporins.

Presently, most of the β-lactam antibiotics used are prepared bysemi-synthetic methods. These β-lactam antibiotics are obtained bymodifying a β-lactam product obtained by fermentation by one or morereactions.

Clavulanic acid and its alkaline metal salts and esters, another type ofβ-lactam compound than the penicillin and cephalosporin, act asβ-lactamase inhibitors, able to enhance the effectiveness of penicillinsand cephalosporins. Clavulanic acid has been applied therefore inpharmaceutical compositions to prevent inactivation of β-lactamantibiotics. For example, the antibacterial activity profile ofamoxicillin is enhanced by the use of potassium clavulanate asβ-lactamase inhibitor. A combination preparation of amoxicillintrihydrate with potassium clavulanate (Augmentin®) is well known.

It is generally known that antibiotic compounds in powder form are notsuitable for formulation purposes, because generally these powdersperform badly as far as flowability is concerned which causes problemsin the manufacturing of final dosage forms, such as tablets. Accuratedosing of the several ingredients is needed to ensure constant endproduct quality. In case of poor flowabilities, such accurate dosing isdifficult to guarantee. Also, the needle shaped crystals, such as ofpotassium clavulanate, often show a low bulk density. Thus, thecontribution of such crystals to the overall volume of the final dosageform is relatively high.

To overcome these problems, often granules of compounds, for examplepotassium clavulanate with excipients (such as microcrystallinecellulose like Avicel® or silica like Syloid® or Aerosil®) or granulesof composition, for example potassium clavulanate with other activeingredients like amoxicillin trihydrate are made before producing thefinal formulation. Several processes are known to form such granules.For example, in case of wet granulation, potassium clavulanate can bemixed with, for instance, amoxicillin and a binding agent after whichthe mixture is moistened by a solvent, granulated and bounded. Beforetabletting the granules with excipients, the granulates might be sieved.This wet granulation process is economically unattractive, as it usessolvents which must be recovered and/or recycled. It is labourintensive, expensive and time consuming due to the large number ofprocessing steps such as mixing, granulating, sieving, drying etc.Moreover, in case of unstable 1′-lactam compounds such as potassiumclavulanate, wet granulation is problematic due to the use of a solventand high temperature during the drying step of the process.

Another method to granulate poor flowing powders is dry granulation. Asan example, the slugging process can be mentioned as described inInternational patent applications WO 9116893 and WO 9219227. Here,tablets of the poor flowing material with excipients are made andsubsequently broken again and sieved to produce granules. Anotherexample of dry granulation is the compaction process as described inInternational patent application WO 9528927. In this application, aprocess has been mentioned wherein compacted granules of a β-lactamantibiotic, for example amoxicillin, and a mixture of an active β-lactamantibiotic and a secondary pharmaceutically active agent, for examplepotassium clavulanate with excipients are made using roller compacting.Subsequently, the roller compacted flakes are milled, resulting ingranules which can be mixed with excipients to press the final tablets.An advantage compared to the wet granulation is the absence of solvents.However, the dry granulation is relatively time consuming due to a largenumber of processing steps. Also, in case of unstable products, aquality risk exists due to locally high temperatures in the process,e.g. due to abrasion. In case the material is hygroscopic, such aspotassium clavulanate, another disadvantage is the handling of the driedcrystals before and during the granulation process. During thishandling, the product might attract water leading to unwanteddegradation reactions. Also a major disadvantage of roller compactedproducts is the relatively large amount of fines which should be removedusing sieving techniques to improve the flowability of such products.Furthermore, difficulties one may encounter by using dry granulationare:

-   -   a lot of dust is produced during the slugging or roller        compaction process and in some cases, for example such as        amoxicillin, this dust sticks to the coarser particles and can        not be separated by currently applied vibrating sieves,    -   dust may deteriorate the flow properties of agglomerates,    -   dust is also responsible for air born β-lactam antibiotics        particles which can cause allergic reaction.

Granules of the active ingredient in the presence of excipients areproduced by the process mentioned above. It would be advantageous tohave the possibility to produce granules of the pure active ingredient.In that case, the production process can be more flexible and possiblyoverall less excipients are necessary. Also the production of finaldosage forms will be more flexible. In case of hygroscopic substancessuch as potassium clavulanate, however, it will be difficult togranulate using one of the above processes without the presence ofexcipients like microcrystalline cellulose or silica, as the latter areknown to protect the hygroscopic potassium clavulanate by removing thefree water from it and, thus, keeping the water activity of suchcompositions low. However, in the International patent application WO9733564 a method has been mentioned in which granules of a pure activeingredient, without the presence of excipients, are made by extrusion.Here, a paste is made of the crystalline powder by adding a liquidwherein the powder is insoluble or slightly soluble. The paste iskneaded then and extruded in a double screwed extruder, after which thegranules are dried. The process again is not suitable for unstableproducts, as locally the temperature in the extruder is high (up to 80°C.). Also, this wet material should be dried at elevated temperatures.

Another method to improve the flowability of needle shaped crystals,especially in the case of potassium clavulanate, is to agglomerate themduring crystallisation to the so-called rosette form as described inEuropean patent EP 277008 B1. In this case, a plurality of needlecrystals radiate out from a common nucleation point. The rosettes showan increased flowability compared to the needles. However, a largedisadvantage of these types of granules is the inclusion of impurities,leading to a decreased chemical quality of the product. Also, theincluded impurities probably increase the degradation rate of theβ-lactam compound, thus resulting in an even worse chemical qualityduring storage.

The object of the invention is to provide a valuable form of a β-lactamantibiotic compound and a process to prepare such a compound thatovercomes most of the above mentioned disadvantages.

Surprisingly, it has been found that novel agglomerates in crystallineform of β-lactam antibiotics in a liquid phase are produced through acrystallisation process when a solution of at least one β-lactamcompound in a solvent or in a mixture of solvents under stirring ismixed together with one or more anti-solvents. Preferably, one or bothsolutions contain water.

DESCRIPTION OF THE FIGURE

An Electron-microscope photo of potassium clavulanate agglomerates asprepared according to Example 9 is shown in the Figure.

SUMMARY OF THE INVENTION

The present invention provides agglomerates in crystalline formcomprising one or more β-lactam compounds having at least one β-lactamcompound of a high water affinity, and optionally contain one or moreexcipients. Preferably, said agglomerates comprise clavulanic acid or apharmaceutically acceptable salt thereof like potassium clavulanate.Further, the agglomerates comprising potassium clavulanate may containamoxicillin as the active β-lactam antibiotic compound. The termagglomerate refers to clustering of the crystals of a compound.

The excipients are microcrystalline cellulose, preferably Avicel®, orsilica, preferably Syloid® or Aerosil®.

The said agglomerates can also be of sterile form.

The new agglomerates are of an average particle size between about 1 μmand 1500 μm, preferably between about 500 μm and 1500 μm, morepreferably between 800 μm and 1200 μm, or between 1 μm and 300 μm,preferably between 1 μm and 200 μm.

Moreover, the agglomerates of the present invention are substantiallyfree from non-agglomerated β-lactam crystals, for instance,non-agglomerated crystals having a weight percentage between 0–10%.

Furthermore, a process to prepare said agglomerates has been providedfor. The agglomerates are produced in a liquid phase medium, whichprocess involves mixing together a solution or suspension of at leastone β-lactam compound corresponding to the β-lactam compound to beprepared in agglomerate form in a solvent or in a mixture of solventsunder stirring with one or more anti-solvents, whereby at least one ofboth solvents and co-solvent contains water. The overall weight ratio ofthe solution containing the β-lactam compound to anti-solvent is about0.05 to 10%. The solvent is for instance water or ethanol and theanti-solvent a ketone, like acetone, methylethylketone,methylisobutylketone or an ester, like methyl acetate, ethyl acetate,isopropyl acetate, butyl acetate or an alcohol, like 1-propanol,1-butanol, 2-butanol, 2-methyl-1-propanol or a mixture of thesesolvents. The pH of the solution of the β-lactam compound may beadjusted to neutral. Preferably, the solvent is water or ethanol and theanti-solvent is acetone or ethyl acetate with some water present in atleast the solvent or the anti-solvent. It is possible also to add otheringredients in one of the streams (solvent, anti-solvent or mixturethereof), either suspended or dissolved.

During the preparation of the agglomerates, one or more stirring devicesare used to crystallise, agglomerate and deagglomerate, or tocrystallise and agglomerate, or to crystallise and deagglomerate theβ-lactam compound and optionally classification and blending withexcipients and/or another β-lactam compound in a batch or continuousoperation in one or more reaction vessels or in one integrated step.Furthermore, the operation is performed by applying stirring devices inone or more vessels, in-line mixers or a combination thereof.Furthermore, it is possible to use a high shear mixer during thepreparation of these agglomerates. Also, agglomerates with variousparticle sizes can be prepared by using a nozzle-sprayer for theβ-lactam containing solution.

The agglomerates of various particle sizes are regulated by furtherusing a combination and permutation of different stirring devices andtheir speed, the type and amount of the solvents used and the way ofmixing of the solvents.

Agglomerates of potassium clavulanate of the present invention show agood level of stability and hygroscopicity.

The agglomerates, prepared according to the present invention, with oneor more pharmaceutical acceptable excipients are suitable forpharmaceutical formulations.

Pharmaceutical formulations comprising amoxicillin, preferablyamoxicillin trihydrate and the crystalline agglomerates of potassiumclavulanate of the present invention and optionally one or morepharmaceutically acceptable inert excipients form another aspect of thepresent invention.

Also, a pharmaceutical formulation, comprising crystalline agglomeratesof amoxicillin trihydrate and potassium clavulanate and one or morepharmaceutically acceptable inert excipients can be made.

The agglomerates, prepared according to the present invention, aresuitable to prepare oral dosage forms such as tablets, capsules, syrupsor sachets, dry instant or ready to use in multiple or single dose form.According to another embodiment of the invention, the oral dosage form,comprising agglomerates or granules of amoxicillin with or without oneor more excipients can also contain a β-lactamase inhibitor such aspotassium clavulanate, preferably in the agglomerated form. Saidagglomerates can also be used in Dose Sipping devices.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides economically interesting agglomerates incrystalline form of a β-lactam compound. The β-lactam compounds are forinstance clavulanic acid but one can also think of amoxicillin orampicillin. The compound can be in the salt form, such as amine oralkaline metal salt. Preferably, agglomerates of potassium clavulanateare produced.

The agglomerates of said invention have an average particle size betweenabout 1 μm and 1500 μm, preferably between about 500 μm and 1500 μm,more preferably between 800 μm and 1200 μm, or between 1 μm and 300 μm,preferably between 1 μm and 200 μm.

Furthermore, said agglomerates are preferably substantially free fromnon-agglomerated β-lactam crystals, as for instance in the needle form.By substantially free from non-agglomerated crystals is meant that theagglomerates have a weight percentage between 0–10% of non-agglomerates.

A process for the preparation of the agglomerates, wherein one or moreβ-lactam compounds with or without excipients are used, consists of acrystallisation procedure to build up agglomerates. The processcomprises mixing together a solution or suspension of one or moreβ-lactam compounds corresponding to the agglomerates to be produced in asolvent or in a mixture of solvents with one or more anti-solvents understirring. The combination of solvent and anti-solvent can result in anemulsion. In the solvent or anti-solvent an amount of water should bepresent, for instance in an amount of 0.05 to 10%. Thereafter, theagglomerates are filtered off, washed and dried. The agglomerates, thusproduced in high yield, maintain the quality criteria set and are highlysuitable for further processing. For the present application, aanti-solvent is defined as a liquid in which the β-lactam compound doesnot dissolve or dissolves only poorly.

More in detail, the β-lactam compound, for instance potassiumclavulanate, is dissolved or suspended in an appropriate solvent or amixture of (partly) miscible solvents, such as water, alcohols, likeethanol, methanol, 1-propanol, 2-butanol, 2-methyl-propanol, ketones,like acetone, methylethylketone, methylisobutylketone, or an ester, likemethyl acetate, ethyl acetate, butyl acetate, with at least a smallamount of water present. Sometimes an emulsion is formed during theagglomeration process. Optionally, the pH of the solution is adjusted toabout neutral, namely to pH 5.0–7.5 by adding an acid, as for instanceacetic acid or ethylhexanoic acid. The way of dissolution will be knownto those skilled in the art and will depend on the stability of theβ-lactam compound in the solvent or in a mixture of solvents. In casewater is used as the only solvent for the dissolution of potassiumclavulanate, residence time and temperature should be as low as possibleand a technique such as in-line mixing, for example a static mixer, canbe attractive. If for example acetone is present, a residence time ofseveral hours might be acceptable.

The β-lactam compound, for example potassium clavulanate, present in thesolvent dissolved or in suspension or in both forms, is contacted with aanti-solvent such as ketone, like acetone, methylethylketone,methylisobutylketone, or an ester, such as methyl acetate, ethylacetate, butyl acetate or a mixture thereof, or an alcohol such as1-propanol, 2-butanol, 2-methyl-propanol optionally containing a solventfor the β-lactam compound, such as water or an alcohol, like methanol orethanol for potassium clavulanate. The overall weight ratio of thesolution containing the β-lactam compound to the anti-solvent depends onthe combination of solvents and on the desired agglomerate diameter, butgenerally lies within 0.05–10%. Also, it is possible to adjust thisratio by adding some solvent to the crystalliser before or during theprocess. This ratio will influence the average diameter of theagglomerates: the higher the relative volume of the solvent, the largerthe agglomerates will be.

Several methods of mixing can be applied and will be known to thoseskilled in the art. For example, the solution of the β-lactam compound,for instance a potassium clavulanate solution and the anti-solvent canbe added simultaneously to the crystalliser or the solution of theβ-lactam compound, for instance a potassium clavulanate solution can beadded to the anti-solvent or the anti-solvent can be added to thesolution of the β-lactam compound, for instance a potassium clavulanatesolution. The temperature should be kept below 50° C. The use of seedingmaterial can also be advantageous to enhance the agglomeration process.

The method of contacting the potassium clavulanate containing solutionand the anti-solvent can be controlled via specific equipment, such asspray nozzles or capillaries. This contacting can occur in a vessel orin line or in a recycling loop over the vessel. It is also possible tofirst form droplets of solution of a certain diameter, after which thedroplets are contacted with the anti-solvent.

Parameters such as the amount of nozzles, their diameter, the flowthrough the nozzles and the rotational speed of the mixer can be used tocontrol the average particle size and density. In this way, severalgrades of agglomerates can be produced, with different physicalproperties.

The method of agitation is determined by the desired agglomeration sizeof the β-lactam compound. In case of relatively large agglomerates(order of magnitude of 1000 μm), the agitation should be moderate. Forexample a common turbine agitator or pitched blade agitator can be used.Here, the general scales up parameters for agitation apply: the diameterof the blades versus the diameter of the vessel should be between0.2–0.9, preferably between 0.2–0.5, depending on the type of agitatorused. The rotational speed (and thus shear), tip velocity, the size ofthe nozzle sprayer and power input determine the agglomerate size anddensity and can be used as control parameters. In case the desiredagglomerate diameter is small, for example 50–100 μm, high speedagitators, such as toothed disks or rotor-stator mixers with multiplestage mixing/shearing action can be used. It is also possible to usein-line high shear mixers, with the advantage of short residence times.If needed, a recycle loop can be applied over such an in-line system.Another possibility is to combine a moderate shear mixer with a highshear mixer or a mill. For example, agglomerates with a diameter of theorder of a magnitude of 1000 μm can be deagglomerated during thecrystallisation using a high shear mixer, which is situated in the samecrystalliser (such as mounted in the bottom) or as a separate unit afterthe crystalliser. Also, for example a colloid mill can be placed afterthe crystalliser for the same purpose. Moreover, the simultaneouscrystallisation/agglomeration technique can be combined using ultrasoniccrystallisation. This technique has been described for instance inPharmaceutical Technology Europe, 9(9), 78 (1997). In this way differentgrades concerning particle size distribution, density, porosity andflowability can be easily achieved.

Generally, the residence time in the crystalliser and/or deagglomeratoris determined by the desired average diameter of the agglomerates. Forpurposes of precipitation/crystallisation, long ageing times are notneeded, as the crystals are formed immediately after contact with theanti-solvent. For agglomeration and deagglomeration, however, a certainminimum and maximum residence time will be valid, depending onparameters such as mixing time and volume of the vessel.

One of the embodiments of the invention is to have the excipientsincluded in the agglomerates by addition of the same before, after orduring the precipitation and/or agglomeration, such as cellulose,preferably microcrystalline cellulose, more preferably with a wateractivity <0.2 at 25° C., most preferably Avicel® PH112. Also, amorphoussilica (Syloid®) or colloidal silicon dioxide (Aerosil®) can be used asexcipient. All methods of mixing are possible: for example the excipientcan be added before, simultaneously or after the addition of theβ-lactam compound solution or (partly) suspension to the crystalliser.The excipients can be added as dry matter, suspended or dissolved in asolvent, preferably one of the solvents (or a mixture thereof) which isalready used in the agglomeration process. An extra advantage of theaddition of such excipients is the positive influence on theagglomeration formation, as they can act as some kind of seedingmaterial.

Another embodiment of the present invention is that the crystallisationand agglomeration can occur in the presence of another active β-lactamingredient, for example amoxicillin trihydrate besides potassiumclavulanate. The amoxicillin can either be added as a solution orsuspension leading to co-crystallisation, similar to the agglomerationin the presence of excipients.

The agglomerates of the present invention are not of the rosette type:they consist of small crystals clustered together in a random order (seethe Figure). Depending on the method of agitation, method of additionand amount of water, the agglomerate size can easily be adjusted betweenabout 1 and 1500 μm and also relatively small particles as with anaverage size of 100 μm or relatively large particles with an averagesize of 1000 μm may be prepared. Compared to, for example, drycompaction, the amount of fines that either must be discharged of orthat must be recycled, is small. The agglomerates can easily beseparated by for example, filtration or centrifugation and subsequentlydried using conventional methods such as tumbling drying. It is alsopossible to include a classification process. For example, agglomeratesof the desired size can be selectively removed from the crystalliserusing gravity and/or a sieve. Fines or large particles which can beremoved by sieving as well, can be recycled, either by addition insuspension or solution to the next batch.

If necessary, pH-adjustment in order to adapt the pH of the end productcan be achieved by adding an acid or base to the solution or theanti-solvent before contacting the streams of solvents containing theβ-lactam compound and the anti-solvent. Also, acid or base can be addedduring the precipitation/crystallisation/ agglomeration process or evenafter the process.

Surprisingly, the process of the present invention produces agglomerateswith a high bulk density, an improved flowability and lesscompressibility, which can be regulated. For example, potassiumclavulanate agglomerates produced can have a loose bulk density betweenabout 0.20 and 0.60 and a tapped bulk density between about 0.50 and0.90 g/ml and a compressibility between about 10 and 40%.

Due to the excellent flowability of the agglomerates prepared using theabove method, they can be used for, for example, direct compression oftablets without the need for further pre-granulation. Moreover, due tothe decreased surface area of the agglomerates, the degradation causedby chemical reactions on the surface (e.g. with water) may be reduced.The level of impurities in the agglomerates is also equal to or evenlower than in case of conventional needles type crystals. As the bulkdensity increases significantly, large advantages can be achieved in thetransportation as well as in the tabletting process: the final tabletvolume can decrease significantly when using agglomerates compared tousing needles.

The energy consumption of the present process is low, as thecrystallisation process which is commonly present in the down streamprocess of pharmaceuticals can be combined with the agglomerationprocess. Moreover, it is possible to combine the usual operationscomprising purification and separation by precipitation orcrystallisation, agglomeration and deagglomeration, classification andblending with e.g. excipients in one unit. The temperatures can be keptbelow 50° C. during the complete agglomeration process, excipients-freeagglomerates can be produced and handling of dry solids before thegranulation does not occur, which is an important advantage in case ofhygroscopic materials. The solvents needed for the agglomeration caneasily be recycled, possibly without the need for purification.Moreover, the possibility to make pure agglomerates of an unstable andhygroscopic product such as potassium clavulanate is highly attractive.

The agglomerates of the present invention can be used for allformulations to produce chew, swallow, disperse, effervescent or normaltablets of all sizes, forms and weights, also to fill hard gelatinecapsules and to formulate dry syrups and for administering drugs withthe help of a dose sipping device. These agglomerates can also be used,for instance, in a pharmaceutical composition as a tablet of amoxicillintrihydrate produced from agglomerates of amoxicillin trihydrate andpotassium clavulanate. For the preparation of sterile agglomerates, thesolution of the β-lactam compounds, solvent and anti-solvent aresterilely filtered prior to crystallisation/agglomeration. Also, thesterile agglomerates substantially free of non-agglomerates, formanother aspect of the present invention.

The invention will now be described with reference to the followingExamples, which are not to be constructed as being limiting on theinvention, and are provided purely for illustrative purposes.

EXAMPLE 1

Preparation of Agglomerates of Potassium Clavulanate (Batch Process).

In a 5-liter flask equipped with a mechanical stirrer, a thermometer andinlet for nitrogen, 4 liters of acetone were placed. A solution ofpotassium clavulanate (60 g.) in a mixture of water/acetone (120 g, 1:1w/w) was added in 30 min at 20° C. under stirring.

The solid material was filtered off and dried in vacuum at 30° C. during2–3 hours to give agglomerates of potassium clavulanate with an averagediameter in the range of 100–1000 μm and a yield of 98%.

EXAMPLE 2

Preparation of Agglomerates of Potassium Clavulanate (Semi-ContinuousProcess).

In a 2-liter flask equipped with a mechanical stirrer, a thermometer andinlet for nitrogen, acetone (1000 ml) and water (10 ml) were placed.Simultaneously a solution of potassium clavulanate (60 g) in a mixtureof water/acetone (120 g, 1:1 w/w) and acetone (4000 ml) was added inabout one hour, while agitating.

During the addition the content of the vessel was kept at about 1800 mlby periodically removing suspension through an outlet. Thereafter, thesolid material was filtered off, washed with dry acetone and dried invacuum at 30° C. during 2–3 hours to yield potassium clavulanateagglomerates with an average diameter in the range of 500–1500 μm.

EXAMPLE 3

Preparation of Agglomerates of Potassium Clavulanate by using a TurbineStirrer Without Baffles in the Reaction Vessel.

Acetone (300 ml) and water (3 ml) were placed in a glass cylinder (100mm in diameter, 150 mm height) equipped with a turbine stirrer (40 mmdiameter), a two dropping funnel and a nitrogen inlet tube. Understirring (900 rpm) simultaneously a solution of potassium clavulanate(30 g) in a water/acetone mixture (60 g, 1:1 w/w) and acetone (2000 ml)were added.

During the addition, the contents of the vessel were kept at about 900ml by removing a part of the contents with the help of an outlet. Afterthe completion of the additions, the solid material was filtered off,washed with dry acetone and dried in vacuum at 30° C. Agglomerates ofpotassium clavulanate with an average particle diameter of 1000 μm wereobtained in 98% yield.

EXAMPLE 4

Preparation of Agglomerates of Potassium Clavulanate by using TurbineStirrer with Baffles in the Reaction Vessel.

The experiment was repeated as described in Example 3, but using avessel with four baffles with a width of 10 mm. Potassium clavulanateagglomerates with an average diameter in the range of 500–1000 μm wereobtained.

EXAMPLE 5

Preparation of Agglomerates of Potassium Clavulanate by using aUltra-Turrax Mixer.

Acetone (500 ml) and water (5 ml) were placed in an one liter 4-neckedround-bottom flask equipped with a thermometer, Ultra-Turrax mixer (typeT25 and shaft S25N-18G), two dropping funnels and a nitrogen inlet tube.

Under mixing (8000 rev/min) simultaneously a solution of potassiumclavulanate (30 g.) in a water/acetone mixture (60 g. 1:1 w/w) andacetone (2000 ml) was added in one hour at 15–20° C. During theaddition, the contents of the vessel were kept between 700 and 800 ml byremoving a part of the content with the help of an outlet.

After the completion of the additions, the solid material was filteredoff, washed with acetone and dried in vacuum at 30° C. Agglomerates ofpotassium clavulanate with an average diameter in range of 50–250 μmwere obtained.

EXAMPLE 6

Preparation of Agglomerates of Potassium Clavulanate by using SilversonL4RT Mixer.

The experiment was repeated as described in Example 5, but using arotor-stator type high shear mixer (Silverson mixer with emulsionscreen, i.e. a screen with spherical pores of about 1.5 mm) at 3000rev/min.

Agglomerates of potassium clavulanate with an average diameter in therange of 10–200 μm were obtained.

EXAMPLE 7

Preparation of Agglomerates of Potassium Clavulanate in Ethyl Acetate.

Ethylacetate (400 ml) and water (1 ml) were placed in a glass cylinder(100 mm in diameter, 150 mm height) equipped with a turbine stirrer (40mm diameter), a two dropping funnel and a nitrogen inlet tube. Understirring (900 rpm) at the same time a solution of potassium clavulanate(10 g) in water (10 ml) and ethyl acetate (600 ml) were added.

After the completion of the additions the solid was filtered off, washedwith dry ethyl acetate and dried in vacuum at 30° C. to giveagglomerates with an average diameter in the range of 500–1500 μm.

EXAMPLE 8

Comparison of Agglomerates and Needles of Potassium Clavulanate,Optionally Mixed with Avicel PH112.

The agglomerates of potassium clavulanate were prepared as described inExample 6, but using a Silverson mixer with general purposedisintegrating screen, i.e. a screen with square holes with a diameterof about 2.5 mm. In a 2- liter flask equipped with the Silverson mixer,a thermometer and inlet for nitrogen acetone (1000 ml) and water (10 ml)were placed. Under mixing (3400 rev/min) simultaneously a solution ofpotassium clavulanate (120 g) in a mixture of water/acetone (240 g, 1:1w/w) and acetone (8000 ml) were added at 15–20° C. During the additionthe contents of the vessel was kept at about 1800 ml with an outlet.After completion of the additions the solid was filtered off, washedwith acetone and dried in vacuum at 30° C. during 2–3 hours to giveagglomerates with an average diameter in the range of 40–200 μm.

Needles of potassium clavulanate were prepared by suspendingdiclavulanate salt of bis(2-dimethylaminoethyl) ether (100 g) in acetone(3350 ml) and water (50 ml). Under stirring a solution of potassium2-ethylhexanoate (1450 ml, 0.34 M) in acetone at 5–10° C. was added.After 1 hour stirring the mixture was filtered off, washed with dryacetone and dried in vacuum during 18 hours at room temperature to give81.2 g of potassium clavulanate needles.

A comparison of physical properties of potassium clavulanate inagglomerated and needle form, optionally mixed with Avicel PH12 in aratio of 70: 30 w/w % have been described in Table 1.

TABLE 1 Comparison of physical properties of potassium clavulanate inagglomerated and needle form, optionally mixed with Avicel PH112 Com-Loose bulk Tapped bulk pres- Particle size Material density densitysibility distribution Agglomerates of 0.49 g/ml 0.68 g/ml 28% between 1and potassium 200 μm clavulanate Needles of 0.18 g/ml 0.36 g/ml 50%between 5 and Potassium 75 μm clavulanate Agglomerates of 0.43 g/ml 0.61g/ml 29% Not determined potassium clavulanate mixed with Avicel PH112Needles of 0.20 g/ml 0.40 g/ml 50% Not determined potassium clavulanatemixed with Avicel PH112

EXAMPLE 9

Preparation of Agglomerates of Potassium Clavulanate in Acetone/Water ata Speed of the Agitator of 3000 RPM.

A solution of potassium clavulanate was made by dissolving circa 5 kg ofpotassium clavulanate in 10 l aqueous acetone (acetone:water=50:50 w/w).This solution, which was kept at 5° C. was pumped through a 0.9 mmnozzle to a crystalliser equipped with a high shear mixer and containing50 l of acetone. Simultaneously, acetone was added to the crystalliserwith a volume ratio compared to the solution of circa 21. During theprocess, the rotational speed of the agitator was 3000 RPM and thetemperature was circa 15° C. The agglomerated suspension was removedcontinuously from the crystalliser, centrifuged, washed with dry acetoneand dried in vacuum at 30° C. In this way, agglomerates such as shown onthe Figure were produced with a loose bulk density of 0.22 g/ml, atapped bulk density of 0.30 g/ml and a compressibility of 27%. Theparticle size distribution is given in Table 2 and a photo made by anElectron-microscope of potassium clavulanate is shown in the Figure.

TABLE 2 Particle size distribution [volume %] 500– <75 μm 75–150 μm150–250 μm 250–500 μm 710 μm >710 μm 46.3 43.3 8 1 0.2 0.1

EXAMPLE 10

Influence of the Agitator Speed during Agglomeration on the PhysicalProperties of the Agglomerates.

A solution of potassium clavulanate was made by dissolving circa 10 kgof potassium clavulanate in 20 l aqueous acetone (acetone:water=50:50w/w). This solution, which was kept at 5° C. was pumped through a 2.5 mmnozzle to a crystalliser equipped with a high shear mixer and containing40 l of acetone. Simultaneously, acetone was added to the crystalliserwith a volume ratio compared to the solution of circa 22. During theprocess, the rotational speed of the agitator was increased from 1000RPM to 2000 RPM and the temperature was circa 15° C. Continuously, thesuspension was removed from the crystalliser using a pump. The twoagglomerated suspensions made were centrifuged, washed with dry acetoneand dried in vacuum at 30° C. The physical properties can be seen inTable 3.

TABLE 3 Physical properties: particle size distribution [volume %] Loosebulk Tapped bulk density density Compressibility [g/ml] [g/ml] [%] <75μm 75–150 μm 150–250 μm 250–500 μm 500–710 μm >710 μm 1000 RPM 0.39 0.4411 5.1 6.5 20.7 60.8 6.1 0.2 2000 RPM 0.42 0.47 11 1.8 2.4 9.5 57.3 271.5

EXAMPLE 11

Influence of the Flow Upon Addition to Crystalliser on the PhysicalProperties of the Agglomerates.

Two experiments were performed in which all parameters were keptconstant, except the flows of the solution and acetone to thecrystalliser. In both experiments, a solution of potassium clavulanatewas made by dissolving circa 5 kg of potassium clavulanate in 10 laqueous acetone (acetone:water=50:50 w/w). This solution, which was keptat 5° C. was pumped through a 0.9 mm nozzle to a crystalliser equippedwith a high shear mixer and containing 30 l of acetone. Simultaneously,acetone was added to the crystalliser with a volume ratio compared tothe solution of circa 21. During the process, the rotational speed ofthe agitator was 3000 and the temperature was circa 15° C. In the firstexperiment, the solution flow was 15 l/h and the acetone flow was 312l/h. In the second experiment, the flows were decreased by A factor 2.Continuously, the suspension was removed form the crystalliser using apump. The two agglomerated suspensions made were centrifuged, washedwith dry acetone and dried in vacuum at 30° C. The physical propertiescan be seen in Table 4.

TABLE 4 Physical properties: Particle size distribution [volume %] Loosebulk Tapped bulk density density Compressibility [g/ml] [g/ml] [%] <75μm 75–150 μm 150–250 μm 250–500 μm 500–710 μm >710 μm High flow 0.270.36 25 48.7 41.2 9.3 0.3 0 0 Low flow 0.35 0.44 20 48.8 50.4 1.1 0.60.4 0

EXAMPLE 12

Influence of the Nozzle Diameter Through which the Potassium ClavulanateSolution is Pumped on the Physical Properties of the Agglomerates.

Two experiments were performed in which all parameters were keptconstant, except the diameter of the nozzle through which the potassiumclavulanate solution is added to the crystalliser. In both experiments,a solution of potassium clavulanate was made by dissolving circa 5 kg ofpotassium clavulanate in 10 l aqueous acetone (acetone:water=50:50 w/w).This solution, which was kept at 5° C., was pumped through either a 0.9mm or 1.2 mm nozzle to a crystalliser equipped with a high shear mixerand containing 50 l of acetone. Simultaneously, acetone was added to thecrystalliser with a volume ratio compared to the solution of circa 21.During the process, the rotational speed of the agitator was 3000 andthe temperature was circa 15° C. Continuously, the suspension wasremoved from the crystalliser using a pump. The two agglomeratedsuspensions made were centrifuged, washed with dry acetone and dried invacuum at 30° C. The physical properties can be seen in Table 5.

TABLE 5 Physical properties: particle size distribution [volume %] Loosebulk Tapped bulk Nozzle density density Compressibility diameter [g/ml][g/ml] [%] <75 μm 75–150 μm 150–250 μm 250–500 μm 500–710 μm >710 μm 0.9mm 0.22 0.3 0.27 46.3 43.3 8 1 0.2 0.1 1.2 mm 0.36 0.44 0.18 15.9 50.631.3 1.9 0 0.3

1. A process for preparing an agglomerate of potassium clavulanate,comprising; a) dissolving or suspending a potassium clavulanate crystalin a solvent or mixture of solvents in the presence of water to form asolution or suspension; b) contacting said solution or suspension withan anti-solvent using a nozzle sprayer and under stirring using astirring device thereby precipitating an agglomerate of potassiumclavulanate having a weight percentage of between 0% and 10% potassiumclavulanate crystals in the needle form, and with the proviso that therosette-like crystalline form of potassium clavulanate is excluded.
 2. Aprocess according to claim 1, wherein the ratio of the weight of thesolution containing the potassium clavulanate to the anti-solvent isabout 0.05 to 10 wt. %.
 3. A process according to claim 1, wherein thesolvent is water, ethanol, or a mixture thereof.
 4. A process accordingto claim 1, wherein the anti-solvent is a ketone, an ester, or analcohol, or a mixture thereof, optionally containing water.
 5. A processaccording to claim 1, wherein the stirring is performed by applyingstirring devices in one or more vessels, in-line mixers or a combinationthereof.
 6. A process according to claim 5, wherein the stirring deviceis a high shear mixer.
 7. A process according to claim 1, wherein saidstirring is performed by combining and permuting different stirringdevices, the speeds of said devices, the type and amount of the solventsused, and mixing one or more solvents and anti-solvents.
 8. A processaccording to claim 1, wherein the agglomerate has an average particlesize between about 1 μm and 1500 μm.
 9. A process according to claim 1,wherein the process comprises dissolving the potassium clavulanate in asolvent, adjusting the pH to about neutral and mixing with theanti-solvent.
 10. A process according to claim 8, wherein theagglomerate has an average particle size about 100 μm.
 11. A processaccording to claim 8, wherein the agglomerate has an average particlesize about 1000 μm.
 12. A process according to claim 1, wherein theagglomerate has a bulk density between about 0.20 g/mL and 0.60 g/mL.13. A process according to claim 1, wherein the agglomerate has acompressibility between about 10% and 40%, calculated as 100 times theratio of the difference between tapped bulk density and loose bulkdensity to the tapped bulk density.
 14. A process according to claim 1,wherein the agglomerate further comprises amoxicillin.
 15. A processaccording to claim 1, wherein the agglomerate optionally contains one ormore excipients.
 16. A process according to claim 15, wherein the one ormore excipients are selected from the group consisting ofmicrocrystalline cellulose and silica.
 17. The process of claim 1,wherein the solvent is aqueous acetone.
 18. A process for preparingpotassium clavulanate in the form of an agglomerate, comprisingcontacting a potassium clavulanate crystal in water or ethanol in thepresence of water, and contacting the resulting solution with ananti-solvent using a nozzle sprayer and under stirring using a stirringdevice to cause precipitation of an agglomerate comprising potassiumclavulanate, wherein said agglomerate has a weight percentage of between0% and 10% potassium clavulanate crystals in the needle form, and withthe proviso that the rosette-like crystalline form of potassiumclavulanate is excluded.
 19. The process of claim 18, wherein thepotassium clavulanate in water further comprises acetone.
 20. Theprocess of claim 18, wherein said anti-solvent is acetone or ethylacetate.
 21. The process of claim 1, wherein said solution or suspensionis pumped through said nozzle to a vessel containing said antisolvent.22. The process of claim 21, wherein said vessel is equipped with astirring device.
 23. The process of claim 22, wherein said stirringdevice is a high shear mixer.
 24. The process of claim 21, wherein anadditional portion of antisolvent is simultaneously added to the vessel.